Anti-tumor active 8-(2-, 3-, and 4-pyridyl)purine compounds are disclosed in British Pat. No. 1201997, 8-phenyladenine compounds exhibiting xanthineoxydase inhibitory activity are disclosed in Journal of Medicinal Chemistry, vol. 11, p. 656, 1968, and 9-purinyl hydroxy alkanoic acid derivatives useful as hypocholesterolaemic agents are disclosed in Belgium Pat. No. 737949.
However, there are no disclosures on purine derivatives having antiinflammatory, analgesic, antipyretic or antiallergic activity, or inhibitory activity on platelet aggregation, in the prior art, including the above documents.
Therefore, the purpose of the present invention is to provide novel purine derivatives having antiinflammatory, analgesic, antiseptic and antiallergic activity, and inhibitory activity on platelet aggregation.
As a result of intensive investigations, the present inventors have completed the present invention.
The present invention relates to purine derivatives of the formula: ##STR2## or pharmaceutically acceptable acid addition salts thereof and/or hydrates thereof.
In the above formula (I), R is a hydrogen atom, an alkyl group or a phenyl group which may be optionally substituted by at least one substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group; each of R.sup.1 and R.sup.2 is a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, a cyclic amino alkyl group, an alkenyl group or an aralkyl group, or R.sup.1 and R.sup.2 together with the adjacent nitrogen atom form a heterocycle; and each of R.sup.3 and R.sup.4 is a hydrogen atom or a lower alkyl group.
In this specification, the alkyl group means a straight or branched alkyl group having 1 to 8 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and octyl; the halogen atom means fluorine, chlorine, bromine and iodine. The lower alkyl group means a straight or branched alkyl group having 1 to 4 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. The lower alkoxy group means a straight or branched alkoxy group having 1 to 4 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. The cycloalkyl group means a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cylopentyl,cyclohexyl and cycloheptyl. The hydroxyalkyl group has 1 to 8 carbon atoms in the alkyl moiety and includes, for example, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and 4-hydroxybutyl. The dialkylaminoalkyl group has 1 to 8 carbon atoms in each alkyl moiety and includes, for example, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl. The cyclic aminoalkyl group may have at least one nitrogen atom, which may be substituted by a lower alkyl group or a hydroxyalkyl group, oxygen atom or sulfur atom as other heteroatom in the cyclic amino moiety and has 1 to 8 carbon atoms in the alkyl moiety, and includes, for example, 1-pyrrolidinylmethyl, 2-(1-pyrrolidinyl)ethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-thiomorpholinopropyl, 2 -(1-piperazinyl)ethyl, 2-(4-methyl-1-piperazinyl)ethyl, 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethyl and 2-(4-methyl-1-homopiperazinyl)ethyl. The alkenyl group means a straight or branched alkenyl group having 2 to 8 carbon atoms and includes, for example, vinyl, allyl, isopropenyl, butenyl, pentenyl, 1-methyl-3-butenyl and hexenyl. The aralkyl group means an arylalkyl group and includes, for example, benzyl, 2-phenylethyl and 3-phenylpropyl. The heterocyle formed by R.sup.1 and R.sup.2 together with the adjacent nitrogen atom may have at least one nitrogen atom, which may be substituted by a lower alkyl group or a hydroxyalkyl group, oxygen atom or sulfur atom as other heteroatom, and includes, for example, 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-(2-hydroxyethyl)-1-piperazinyl, 1-homopiperazinyl, 4-methyl-1-homopiperazinyl, morpholino and thiomorpholino.
The compounds of formula (I) of the present invention can, for example, be prepared according to the following methods: (1) A method which comprises reacting a compound of the formula: ##STR3## wherein each symbol is as defined above, with a compound of the formula: ##STR4## wherein X is a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a haloformyl group or a thioamide group and R.sup.4 is as defined above.
The reaction is suitably performed in accordance with the kinds of substituent X of the compounds of formula (III), and is preferably carried out at 0.degree.-250.degree. C. in the presence of a condensation agent such as polyphosphoric acid, polyphosphate ester, phosphorus oxychloride, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, thionyl chloride, phosphorus pentoxide, sodium ethoxide or potassium tert-butoxide, and if necessary, in an inert solvent such as benzene, toluene, xylene, pyridine, ethanol, isopropanol, ethylene glycol, diethylene glycol dimethyl ether, dimethylformamide or dioxane. (2) A method which comprises reacting a compound of the formula: ##STR5## wherein Y is a halogen atom or a lower alkylthio group such as methylthio or ethylthio and the other symbols are as defined above, with a compound of the formula: ##STR6## wherein each symbol is as defined above.
The reaction is carried out at 50.degree.-250.degree. C. under refluxing or in a pressure vessel without solvent or preferably in an inert solvent such as water, toluene, xylene, pyridine, ethanol, isopropanol or dimethylformamide.
The purine derivatives of formula (I) according to the present invention can be provided as a medicine in the form of a free base, an acid addition salt thereof or a hydrate thereof.
A pharmaceutically acceptable acid addition salt thereof can be used as the acid addition salt, and includes, for example, salts of inorganic and organic acids such as hydrochloric, sulfuric, hydrobromic, phosphoric, formic, acetic, oxalic, fumaric, maleic, citric, tartaric, malic, mandelic, methanesulfonic and toluenesulfonic acids.
The compounds of formula (I), the acid addition salts thereof and hydrates thereof exhibit antiinflammatory, analgesic and antipyretic activities, for example, according to the carrageenan foot edema method of Winter et al., phenylquinone writhing method of Hendershot et al. or in guinea pigs having a fever caused by lipopolysaccharide (LPS) according to Kobayashi et al.
Ulcer-inducing effects are not observed in the compounds of the present invention, unlike the acid and nonsteroid antiinflammatory agents such as aspirin, and the compounds of the present invention are useful antiinflammatory agents, analgesics and antipyretics having less side effects.
The compounds of the present invention also inhibit rat adjuvant arthritis of Newbold et al., and are useful in the treatment of rheumatoid arthritis or osteoarthritis.
Further, the compounds of the present invention inhibit the reverse passive arthus reaction according to the method of Plam et al., and are useful in the treatment of various diseases caused by Type III allergic reaction such as rheumatoid arthritis, systemic erythematodes, serum sickness, hypersensitivity pneumonitis or chronic glomeruler nephritis. Furthermore, the compounds of the present invention inhibit the production of SRS-A which is accompanied with phagocytosis of Bordetella pertussis by rat celiac leukocyte according to the partly modified method of D. Rosa et al., and are useful as drugs for the treatment of bronchial asthma. In addition, the compounds of the present invention are useful as improving agents for improving the circulatory function.
The compounds of the present invention can be administered orally or parenterally. In oral administration, the compounds are mixed with a conventional and pharmaceutically acceptable additive such as a carrier, an excipient or a diluent to form powder, tablets, capsules, troches, solutions, syrup and granules. In parenteral administration, the compounds can be used as injectable solution for intraveneous, intramuscular or subcutaneous injections, suppositories or cream ointments in the form of solutions or non-aqueous suspensions.
The single dose may vary depending on the patient's symptoms, body weight or age and so on, but preferably ranges from 0.1 to 10 mg per kg depending on body weight for human adults.